Mutation of the KRAS gene drives up to 30% of all human cancers, and is especially prevalent among aggressive and hard-to-treat forms — like pancreatic, colon and lung cancers. For decades, researchers have tried to develop drugs to shut down the mutated gene, but a lack of success by pharmaceutical, biotech and academic laboratories has earned this cancer mutation a reputation for being “undruggable.”
New research conducted at the University of Michigan, however, offers a new strategy for disrupting the mutations’ unchecked spread — by attacking a protein complex that protects and supports it. The approach, detailed in a forthcoming article in Neoplasia[DI1] , comes as efforts to combat the mutation have been in the national spotlight. Recently, the National Cancer Institute announced a $10 million-a-year initiative to target KRAS, for which it is repurposing a new high-tech lab at the Frederick National Laboratory for Cancer Research.
“It’s a very important but difficult target,” says study author Dipankar Ray, Ph.D., assistant professor of radiation oncology at the U-M Medical School.
The U-M research team demonstrated that disrupting a protein complex called SMURF2:UBCH5 degrades the cancer stimulating forms of KRAS.
“We found that if we can get rid of SMURF2 protein or decrease its activity, the tumor-forming ability of mutant KRAS-driven cells is reduced,” says Ray, who notes that SMURF stands for the enzyme SMAD ubiquitination regulatory factor 2, not the blue color cartoon characters.
“However, because SMURF2 plays a very important role in the functioning of normal cells, we feared that blocking its activity directly would cause too many bad side effects,” he continues. “So, we teamed up with several U-M researchers to develop a new strategy that focuses on disrupting SMURF2’s interaction with another protein called UBCH5 — which KRAS’s stability depends upon. This approach also gets rid of KRAS, but is expected to have fewer side effects for normal tissues.”
Building on these findings, U-M researchers believe it should be possible to design small molecules that would help to move the laboratory results into the clinical setting to kill cancer cells driven by mutant KRAS.
“We are very encouraged by our initial findings that our approach could eventually help us develop a drug capable of treating mutant KRAS-driven cancers,” he says.
Funding: National Cancer Institute grants 5R01CA160981, 5R01CA131290, R01CA154365, 5P30CA46592
Additional U-M Authors: Shirish Shukla, Uday Sankar Allam, Aarif Ahsan, Guoan Chen, Pranathi Meda Krishnamurthy, Katherine Marsh, Matthew Rumschlag, Sunita Shankar, Christopher Whitehead, Matthew Schipper, Venkatesha Basrur, Daniel R. Southworth, Arul M. Chinnaiyan, Alnawaz Rehemtulla, David G. Beer, Theodore S. Lawrence and Mukesh K. Nyati.
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